PROJECT SUMMARY/ABSTRACT Eating disorders, spanning obesity to anorexia, are highly prevalent and problematic in our society. They are difficult to treat, affect a large proportion of the population, and underlie many other causes of morbidity that have become increasingly costly to manage. Furthermore, feeding behavior is upset in multiple psychiatric disorders and weight gain is a common side effect of many psychotropic medications, but the pathophysiology of these effects is unknown. Therefore, the study of feeding behavior and the neurocircuitry of metabolism are of great interest to psychiatry. Using cutting-edge neuroscience tools to build on traditional genetic methods, the applicant proposes a functional mechanism for projections from satiety-associated neurons in the hypothalamus (POMC neurons) to medial prefrontal cortex melanocortin-4 receptor-expressing neurons (mPFCMC4R) in the pathophysiology of overeating related to obesity. In this mouse-based study, the applicant will examine a novel pathway from POMC neurons to the infralimbic region of the mPFC and investigate the relevance to feeding behavior. First, she will determine if mPFCMC4R neurons, and specifically those that receive projections from POMC neurons, play a role in executive function specific to food-related decisions, focusing on set-shifting and rule reversal (Aim 1). Next, she will perform the same behavioral assays while recording the activity of the mPFCMC4R neurons in awake, behaving mice (Aim 2). These studies will employ genetically engineered mice and viruses that together enable temporal and spatial control and study of specific subpopulations of neurons, and will be performed in both male and female mice. Together, these aims will show that the POMC? mPFCMC4R circuit is a key node in the development of overeating behavior, and consider sex-specific vulnerability to overeating at this unique site of integration of feeding behavior and executive function. Further, this work will provide new animal models for future research with dissociable behavior and physiologic outputs as well as potential therapeutic targets which are urgently needed for eating disorders. The applicant, Dr. Rachel Ross, is well qualified to execute the proposed experiments. She is committed to pursuing a scientific career in neuroscience of behavior and has proposed a comprehensive four-year plan to meet her goal of becoming an independent physician-scientist. Dr. Ross will be working under the primary mentorship of Dr. Kerry Ressler with co-mentorship from Dr. Bradford Lowell. She has enlisted a research advisory committee of internationally-recognized experts in neuroscience and psychiatry to support her. The Department of Psychiatry at McLean Hospital (and secondary site of the Division of Endocrinology at Beth Israel Deaconess Medical Center) is an ideal environment for completion of her scientific and career development objectives given the outstanding research community, tradition of scientific discovery, and ongoing dedication to trainee mentorship in this field.